Document Type
Article
Date of Original Version
2003
Department
Cell & Molecular Biology
Abstract
Protein tyrosine kinases (PTK) are key enzymes of mammalian signal transduction. For the fidelity of signal transduction, each PTK phosphorylates only one or a few proteins on specific Tyr residues. Substrate specificity is thought to be mediated by PTK–substrate docking interactions and recognition of the phosphorylation site sequence by the kinase active site. However, a substrate-docking site has not been determined on any PTK. C-terminal Src kinase (Csk) is a PTK that specifically phosphorylates Src family kinases on a C-terminal Tyr. In this study, by sequence alignment and site-specific mutagenesis, we located a substrate-docking site on Csk. Mutations in the docking site disabled Csk to phosphorylate, regulate, and complex with Src but only moderately affected its general kinase activity. A peptide mimicking the docking site potently inhibited (IC50 = 21 μM) Csk phosphorylation of Src but only moderately inhibited (IC50 = 422 μM) its general kinase activity. Determination of the substrate-docking site provides the structural basis of substrate specificity in Csk and a model for understanding substrate specificity in other PTKs.
Citation/Publisher Attribution
Lee, S., Lin, X., Nam, N. H., Parang, K., & Sun, G. (2003). Determination of the substrate-docking site of protein tyrosine kinase C-terminal Src kinase. Proceedings of the National Academy of Sciences, 100(25), 14707-14712. doi: 10.1073/pnas.2534493100
Available at: https://doi.org/10.1073/pnas.2534493100
Comment
Sungsoo Lee and Xiaofeng Lin are in the Department of Cell and Molecular Biology. Nguyen Hai Nam and Keykavous Parang are in the Department of Biomedical Sciences in the College of Pharmacy. And Gongqin Sun has a dual appointment with both departments.
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